Mutations in oncogenes and tumor suppressor genes in animal and human tumors may give important clues as to the exposures that led to the tumors. For rodent neoplasms that are pathologically similar to the corresponding human cancer, the rodent disease may be used to model the cellular events involved and to study prevention and therapy. Currently, we are focusing on the von Hippel-Lindau (VHL) gene in kidney cancer, and the K-ras gene in lung cancer.The VHL tumor suppressor gene is mutated in a high percentage of both familial and sporadic renal cell carcinomas. We have recently established an animal model for causation of VHL mutations in clear cell renal tumors, by the environmental carcinogen N-nitrosodimethylamine. In a parallel study, VHL protein has been expressed in normal rat kidney cells in culture. A remarkable and unanticipated finding, confirmed by both fluorescence microscopy and immunogold electron microscopy, is that the pVHL localizes to the mitochondria. In view of the many roles played by mitochondria in cytokine regulation, angiogenesis, and apoptosis, as well as energy metabolism, this finding may represent the rosetta stone to the functioning of pVHL. In studies of the role of the oncogene K- ras in genesis of adenocarcinoma of the lung, we are utilizing a mouse model, including tumors induced in vivo, and normal immortalized and transformed alveolar type 2 cells in vitro. Among tumors caused in vivo in Swiss mice by N-nitrosodimethylamine, tumors with and without codon 12 K-ras mutation were discovered. We carried out biochemical analyses to test the hypothesis that mutant K-ras p21 would have higher activity, as indicated by ras-GTP, and that activity of the Erk1/2 pathway leading to increased rate of cell division as marked by proliferating cell nuclear antigen (PCNA) would be observed, with resultant increase in tumor size. The results indicate that the hypothesis is almost certainly incorrect. Tumors with mutant K-ras did not have a significant increase in K-ras p21 or Erk1/2 amount or activity, or amount of PCNA, and in fact these tumors were significantly smaller than those without the mutation, and had less PCNA. The tumors with mutant K-ras, but not the others, showed a significant correlation between K-ras-GTP and both tumor size and total Erk1 and 2 protein. PCNA correlated strongly with amounts of c-raf, but not with K-ras-GTP. TUNEL staining failed to reveal significant apoptosis. These results indicate that mutant ras is playing a role in tumor development other than simply stimulation of mitosis, and influences tumor size via mechanisms other than cell death. Further studies of the role of ras in control of cell growth and differentiation are in progress. - Animal models, Lung alveolar epithelia, Lung cancer, Oncogene, Ras, Renal tumors, Tumor suppressor genes, Tumorigenesis, VHL, - Neither Human Subjects nor Human Tissues